Design and Development of IKZF2 and CK1α Dual Degraders.
J Med Chem
; 66(24): 16953-16979, 2023 12 28.
Article
en En
| MEDLINE
| ID: mdl-38085607
ABSTRACT
Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Caseína Quinasa Ialfa
Límite:
Female
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
/
USA